Safety and activity of BTK inhibitor ibrutinib combined with ofatumumab in chronic lymphocytic leukemia: a phase 1b/2 study.

Ibrutinib represents a therapeutic advance in chronic lymphocytic leukemia (CLL) but as monotherapy produces few complete remissions in previously treated patients. Anti-CD20 antibodies have improved response and progression-free survival (PFS) when combined with chemotherapy. We evaluated the safety and activity of adding ofatumumab to ibrutinib in 3 different administration sequences. Patients with CLL/small lymphocytic lymphoma (SLL), prolymphocytic leukemia, or Richter's transformation who failed ≥2 prior therapies were enrolled. Patients received ibrutinib 420 mg daily and 12 doses of ofatumumab 300/2000 mg in 3 schedules: ibrutinib lead-in (group 1; n = 27), concurrent start (group 2; n = 20), or ofatumumab lead-in (group 3; n = 24). Seventy-one patients were treated; most had high-risk disease including del(17)(p13.1) (44%) or del(11)(q22.3) (31%). The most frequent adverse events (any grade) were diarrhea (70%), infusion-related reaction (45%), and peripheral sensory neuropathy (44%). Overall response rates in CLL/SLL patients (n = 66) were 100%, 79%, and 71% in groups 1, 2, and 3, respectively. Estimated 12-month PFSs for all patients were 89%, 85%, and 75%, respectively. Four patients in group 3 progressed prior to receiving ibrutinib. This study demonstrates the tolerability and clinical activity of this combination with quicker time to best response than single-agent ibrutinib and with durable responses. This trial was registered at www.clinicaltrials.gov as #NCT01217749.

Complete response to induction therapy in patients with Myc-positive and double-hit non-Hodgkin lymphoma is associated with prolonged progression-free survival.

BACKGROUND: Myc-positive B-cell non-Hodgkin lymphoma (NHL) with or without a B-cell chronic lymphocytic leukemia/lymphoma 2 (BCL2) rearrangement is associated with inferior progression-free survival (PFS) and overall survival (OS). In this study, the authors reviewed the outcomes of patients with myc-positive and double-hit NHL at The Ohio State University. METHODS: All patients who had non-Burkitt, aggressive B-cell NHL from 2008 to 2011 were assessed for the t(14;18) translocation and for v-myc avian myelocytomatosis viral oncogene homolog (CMYC) rearrangements at diagnosis, and all myc-positive patients were included in the current analysis. Associations with clinical characteristics were described, and univariable and multivariable models were used to assess correlations between clinical variables and outcomes. RESULTS: Of 49 myc-positive patients, 29 patients also had BCL2 rearrangements (double-hit NHL). No patients underwent autologous stem cell transplantation in first remission. For all myc-positive patients, the median PFS was 16.6 months, and the median OS was 37.7 months. For patients who had double-hit NHL, the median PFS was 8 months, and the median OS was 12.5 months; whereas the median PFS and OS were not reached for myc-positive patients. A complete response (CR) after front-line therapy, the presence of t(14;18), International Prognostic Index (IPI) group, and age were associated with PFS; whereas only the achievement of a CR and age >60 years were associated with OS in the multivariable setting. The median PFS was 3.3 months, and the median and OS was 7.0 months for patients who did not attain a CR; and the medians were not reached for patients who achieved a CR (P < .00001). CONCLUSIONS: The achievement of a CR with front-line therapy is associated with a prolonged PFS and OS in patients with myc-positive NHL, even after adjusting for type of initial therapy, histology, age, IPI, or the presence of a concurrent BCL2 translocation.

Reperfusion phenomenon masking acute and subacute infarcts at dynamic perfusion CT: confirmation by fusion of CT and diffusion-weighted MR images.

OBJECTIVE: The purpose of this study was to evaluate cerebral blood flow, cerebral blood volume, mean transit time, time to peak, and delay in a selected sample of patients with visually normal or increased cerebral blood volume to facilitate detection of a postischemic CT perfusion hyperperfusion-reperfusion phenomenon that may mask subacute and acute infarcts. MATERIALS AND METHODS: Ten patients were included who had visually normal or elevated cerebral blood volume in infarcts larger than 1.5 cm confirmed on diffusion-weighted MR images within 48 hours of perfusion CT. The cases were selected from 371 perfusion CT studies of stroke patients (99 associated with positive diffusion-weighted imaging findings) reviewed over 2.5 years on a 64-MDCT scanner. The perfusion CT images were fused to the diffusion-weighted images for measurement of cerebral blood volume, cerebral blood flow, mean transit time, time to peak, and delay in each infarct versus the contralateral hemisphere. Two neuroradiologists reviewed the images in consensus. RESULTS: The mean time between symptom onset and perfusion CT was 3.9 days. Infarcts were in the middle cerebral artery (n = 7) and posterior cerebral artery (n = 3) distributions. Significant differences versus the contralateral finding were found in cerebral blood volume (p = 0.016; mean increase, 30.0%), mean transit time (p = 0.007; mean increase, 38.1%), time to peak (p = 0.005; mean increase, 17.7%), and delay (p = 0.030; mean increase, 124.9%). The difference in cerebral blood flow (p = 0.785; mean increase, 1.8%) was not statistically significant. Infarcts became enhanced on the dynamic perfusion CT images of eight of 10 patients and on the contrast-enhanced T1-weighted MR images of six of nine patients. CONCLUSION: Visual inspection of cerebral blood volume and cerebral blood flow maps alone is insufficient in the evaluation of infarcts. Mean transit time, time to peak, and delay maps also should be reviewed with dynamic source images to prevent misinterpretation of findings as false-negative. This phenomenon is unlikely to occur hyperacutely (< 8 hours after onset).

Multivoxel MR spectroscopic imaging--distinguishing intracranial tumours from non-neoplastic disease.

INTRODUCTION: Multi-voxel MR spectroscopic imaging (MRSI) provides chemical metabolite information that can supplement conventional MR imaging in the study of intracranial neoplasia. Our purpose was to use a robust semi-automated spectroscopic analysis to distinguish intracranial tumours from non-neoplastic disease. MATERIALS AND METHODS: Twenty intracranial tumours and 15 patients with non-neoplastic disease confirmed on histological examination or serial neuroimaging were studied with 2-dimensional MRSI using point-resolved spectroscopic (PRESS) imaging localisation. Using semi-automated post-processing software, spectra were analysed for peak heights of choline (Cho), creatine (Cr), N-acetyl aspartate (NAA), lactate (Lac) and lipid (Lip). Normalised Cho (nCho) ratios, computed by dividing maximum Cho in the lesion by the normal-appearing brain, were compared between intracranial tumours and non-neoplastic disease. RESULTS: Meningiomas displayed homogeneously elevated Cho. Malignant tumours, especially large glioblastoma multiforme, displayed inhomogeneity of metabolites within the tumour. All tumours had elevation of nCho >1 (mean 1.91 +/- 0.65), and non-neoplastic diseases had tumour nCho <1 (mean 0.91 +/- 0.46), which was significantly lower (P <0.05). Two patients with non-neoplastic lesions, one with subacute cerebral infarction and the other with cryptococcoma, had elevated Cho compared to normal tissue (false positive rate 13%). CONCLUSION: Using semi-automated MRSI method, a simplified normalised Cho algorithm provides a method to distinguish intracranial tumours from non-neoplastic disease.

Krabbe disease: unusual MRI findings.

We present the MRI findings in a case of infantile-onset Krabbe disease. Enlargement of the intracranial optic nerves and cervical cord were detected in addition to more typical changes in the cerebral white matter and thalami. We also review the proton MR spectroscopic findings in Krabbe disease.